Pyrido[3,4-B]indole derivatives as serotonergic agents

ABSTRACT

The compound of the formula: ##STR1## where R 1  and R 5  are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO 2  H, C 1  -C 6  alkyl, C 2  -C 10  alkenyl, C 1  -C 6  alkoxy, C 3  -C 8  cycloalkyl, cycloalkylalkyl, C 3  -C 8  cycloalkyloxy, C 2  -C 7  alkylcarbonyl, C 2  -C 7  alkylcarbonyloxy, C 2  -C 7  alkoxycarbonyl, mono- or di-alkylaminocarbonyl, tetrazolyl, --OH, --(CH 2 ) 1-6  OH, --SH, --NH 2  or --(CH 2 ) 1-6  NR 8  R 9  where R 8  is hydrogen, C 1  -C 6  alkyl, C 2  -C 7  alkylcarbonyl, C 2  -C 7  alkoxycarbonyl and R 9  is hydrogen or C 1  -C 6  alkyl; R 2  is hydrogen or C 1  -C 6  alkyl; R 3  and R 4  are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; R 6  and R 7  are independently H, C 1  -C 10  alkyl, C 2  -C 10  alkenyl, C 3  -C 8  cycloalkyl, cycloalkylalkyl or R 6  and R 7  taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof.

BACKGROUND OF INVENTION

The compounds of this invention possess high affinity for the serotonin5-HT_(1A) receptor and as such are useful as antidepressant andanxiolytic agents for the treatment of a variety of central nervoussystem disorders such as depression, anxiety, eating disorders, sexualdisfunction, addiction and related problems. As an example buspirone(U.S. Pat. No. 3,717,634) is known to display potent affinity for the5-HT_(1A) serotonin receptor. Buspirone is used extensively for thetreatment of anxiety and this anxiolytic activity is believed to be due,at least partially, to its 5-HT_(1A) receptor affinity [VanderMaelen etal., Eut. J. Pharmacol. 1986, 129 ( 123-130)].

WO 9,311,122-A and U.S. Pat. No. 4,988,814 exemplify piperazinecompounds with affinity for the 5-HT_(1A) receptor.

DESCRIPTION OF THE INVENTION

This invention relates to a series of novel compounds which haveactivity as serotonergic agents and have the general formula A, ##STR2##where R₁ and R₅ are independently hydrogen, fluorine, chlorine, bromine,iodine, trifluoromethyl, cyano, nitro, CO₂ H, C₁ -C₆ alkyl, C₂ -C₁₀alkenyl, C₁ -C₆ alkoxy, C₃ -C₈ cycloalkyl, cycloalkylalkyl where thealkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to8 carbon atoms, C₃ -C₈ cycloalkyloxy, C₂ -C₇ alkylcarbonyl, C₂ -C₇alkylcarbonyloxy, C₂ -C₇ alkoxycarbonyl, mono- or di-alkylaminocarbonylin which each alkyl group, independently, contains 1 to 6 carbon atoms,tetrazolyl, --OH, --(CH₂)₁₋₆ OH, --SH, --NH₂ or --(CH₂)₁₋₆ NR₈ R₉ whereR₈ is hydrogen, C₁ -C₆ alkyl, C₂ -C₇ alkylcarbonyl, C₂ -C₇alkoxycarbonyl and R₉ is hydrogen or

C₁ -C₆ alkyl;

R₂ is hydrogen or C₁ -C₆ alkyl;

R₃ and R₄ are hydrogen or taken together with the carbon atoms to whichthey, are attached form a double bond;

R₆ and R₇ are independently H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₈cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbon atomsand the cycloalkyl group is 3 to 8 carbon atoms or R₆ and R₇ takentogether are polymethylene, which, with the nitrogen atom to which theyare attached, form a ring of 3 to 8 atoms; or a pharmaceuticallyacceptable salt thereof.

Of these compounds, a preferred group from the viewpoint of facileproduction and economic considerations, are those in which R₁ and R₅,independently, represent hydrogen, fluorine, chlorine, bromine,trifluoromethyl, CO₂ H, C₁ -C₃ alkyl, C₁ -C₃ alkoxy, C₂ -C₄alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkylgroup, independently, contains 1 to 6 carbon atoms, --OH, --NH₂ or--(CH₂)₁₋₃ NR₈ R₉ where R₈ is hydrogen or C₁ C₃ alkyl and R₉ is hydrogenor C₁ --C₃ alkyl; R₂ is H or C₁ --C₃ alkyl; R₃ and R₄ are hydrogen ortaken together with the carbon atoms to which they are attached form adouble bond; and R₆ and R₇, taken together are polymethylene, which,with the nitrogen atom to which they are attached, form a ring of 5 to 8atoms; or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salts are those derived from suchorganic and inorganic acids as: acetic, lactic, citric, tartaric,succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.Where the compounds of this invention contain acidic substituents suchas the carboxylic acid group, salts may be formed with pharmaceuticallyacceptable bases to form alkali metal (such as Na, K or Li), alkalineearth metal (such as Ca or Mg), the ammonium or mono- or dialkylaminesalts, the alkyl portion of said amine salts fits containing 1 to 6carbon atoms.

The compounds of this invention possess one or three chiral centersdepending on the identity of R₃ and R₄. Therefore they presentdiastereoisomers and enantiomers, which may be separated by conventionalprocedures. In naming the compounds throughout this disclosure and inthe appended claims it is to be understood that it is intended toembrace the isomers as their mixtures and in their pure form.

The compounds of this invention are conveniently prepared by the routeshown in the following scheme. Specific examples are given in theExperimental Section. These examples are for illustrative purposes onlyand are not to be construed as limitations for the disclosed invention.Those skilled in the art will be aware of other methods of preparingcompounds of this invention. The starting materials or intermediates areavailable commercially or can be prepared by standard literatureprocedures. ##STR3##

High affinity for the serotonin 5-HT_(1A) receptor for the compounds ofthis invention was established by testing them in accordance with thestandard pharmacological test procedure in which the compound's abilityto displace [³ H] 8-OHDPAT (dipropylaminotetralin) from the 5-HT_(1A)serotonin receptor was determined following the procedure of Hall etal., J. Neurochem. 44 1685 (1985). This procedure is employed toanalogize the properties of the claimed compounds with that ofbuspirone, which is a standard for anxiolytic activity, and, like thecompounds of this invention, displays potent affinity for the 5-HT_(1A)serotonin receptor subtype. The anxiolytic activity of buspirone isbelieved to be, at least partially, due to its 5-HT_(1A) receptoraffinity [VanderMaelen et al., Eur. J. Pharmacol. 1986, 129 (123-130)].The results of this experimental test procedure are given in thefollowing table:

                  TABLE                                                           ______________________________________                                                   5-HT.sub.1A Binding (IC.sub.50)                                    ______________________________________                                        Example 1    30.9 nM                                                          Example 2    33.3 nM                                                          Example 3    37.1 nM                                                          Example 4    67.4 nM                                                          ______________________________________                                    

Hence, the compounds of this invention demonstrated high affinity forthe serotonin 5-HT_(1A) receptor subtype, and are therefore useful inthe treatment of multi-CNS disorders amenable to treatment withantidepressant and anxiolytic agents.

Based upon this receptor binding data, the compounds of this inventionare characterized as anxiolytic and/or antidepressant agents useful inthe treatment of depression and in alleviating anxiety. As such, thecompounds may be administered neat or with a pharmaceutical carrier to apatient in need thereof. The pharmaceutical carrier may be solid orliquid.

Applicable solid carriers can include one or more substances which mayalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders ortablet-disintergrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The dosage to be used in the treatment of a specific patient sufferingfrom depression or anxiety must be subjectively determined by theattending physician. The variables involved include the specific stateof anxiety or depression, and the size, age and response pattern of thepatient.

EXAMPLE 11-Azepan-1-yl-2-phenyl-4-(1,3,4,9-tetrahydro-2H-pyrido[3.4-b]indol-2-yl]-butan-1-one

A mixture of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (520 mg, 3.0mmol), 1-(azepan-1-yl)-4-chloro-2-phenyl-butan-1-one (840 mg, 3.0 mmol),N,N-diisopropylethylamine (520 μl, 3.0 mmol) and potassium iodide (500mg, 3.0 mmol) in 15 ml of anhydrous dimethylformamide was heated undernitrogen at 80° C. for five hours. The reaction was partitioned betweenethyl acetate and water. The aqueous layer was separated and the organiclayer washed five times with water. The organic layer was dried (MgSO₄)and the solvent removed under reduced pressure to give 1.16 g of a brownoil. Purification of the oil on 200 g of silica gel (230-400 mesh)eluting with 75% ethyl acetate-hexane gave 441 mg of a solid foam. Thefoam was dissolved in diethyl ether containing a small amount ofmethylene chloride. To this solution was added 1.1 ml of 1N etherealHCl. An oil precipitated, which after concentration of the supernatantliquid, solidified. The solid was collected by filtration and thenrecrystallized from isopropyl alcohol-ethanol to give 329 mg (22%) ofthe title compound as a light brown solid, hydrochloride, 0.375isopropanolate, 0.375 ethanolate, mp 238°-239° C.

Elemental Analysis for C₂₇ H₃₄ ClN₃ O.0.375C₃ H₈ O.0.375C₂ H₆ O; Calc'd:C,70.51;H,8.04;N,8.54; Found: C,70.51;H,7.86;N,8.75.

EXAMPLE 21-Azepan-1-yl-4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3.4-b]-indol-2-yl]-2-phenyl-butan-1-one

A solution of benzyl chloroformate (8.3 ml, 58 mmol) in 20 ml ofanhydrous tetrahydrofuran was added dropwise under nitrogen to a warmsolution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (10.0 g, 58 mmol)and triethylamine (8.1 ml, 58 mmol) in 200 ml of anhydroustetrahydrofuran. After the addition, the reaction was stirred at roomtemperature for four hours. The solvent was removed under reducedpressure and the residue partitioned between ethyl acetate and 1N HCl.The organic layer was separated, extracted one time with 1N HCl, dried(MgSO₄) and the solvent removed under reduced pressure to give 15.7 g ofan off-white solid. Recrystallization of the solid from 100 ml of 25%hexane-ethyl acetate gave 4.23 g (24%) of the benzyloxycarbonylderivative of the starting material as a white solid. Recrystallizationof the mother liquors from ethyl acetate-diisopropyl ether gave anadditional 5.84 g (33%) of material, mp 102°-104° C.

Elemental Analysis for C₁₉ H₁₈ N₂ O_(2;) Calc'd: C,74.49;H,5.92;N,9.14;Found: C,74.44;H,5.96;N,9.30.

Sodium hydride [1.5 g of a 60% oil dispersion (37 mmol)] was added inportions over fifteen minutes to a solution of the material prepared inthe previous paragraph (9.5 g, 31 mmol) in 100 ml of anhydrousdimethylformamide under nitrogen at room temperature. After the additionwas complete the reaction was stirred for three hours. Methyl iodide(5.8 ml, 93 mmol) was then added and the reaction stirred at roomtemperature overnight. The reaction was quenched by the slow addition of1N HCl. The reaction was then partitioned between 1N HCl and ethylacetate. The organic layer was separated, extracted three times withwater, dried (MgSO₄) and the solvent removed under reduced pressure togive 10.4 g of a light yellow solid. Recrystallization of the solid from100 ml of 20% ethyl acetate-diisopropyl ether gave 7.59 g (76%) of the9-methyl derivative of the starting material as a white solid, mp100°-101° C.

Elemental Analysis for C₂₀ H₂₀ N₂ O₂ ; Calc'd: C,74.97;H,6.29;N,8.79;Found: C,74.95;H,6.30;N,8.77.

A mixture of the material prepared in the previous paragraph (4.0 g, 12mmol) and 500 mg of 10% Pd/C in 40 ml of ethyl acetate was hydrogenatedat room temperature and 40 psi for 5.5 hours. The catalyst was removedby filtration through celite and then rinsed thoroughly with ethanol andthen dimethylformamide. The filtrate was concentrated under reducedpressure to give 2.39 g of an oil. The oil was dissolved in 15 ml ofethanol and 10 ml of 1N ethereal HCl was added. A solid formed which wascollected by filtration, rinsed with diethyl ether, and dried under highvacuum to give 2.23 g (80%) of1,2,3,4-tetrahydro-9-methyl-pyrido[3,4-b]indole as the hydrochloridesalt, mp>250° C.

Elemental Analysis for C₁₂ H₁₅ ClN₂ ; Calc'd: C,64.71H,6.79;N,12.58;Found: C,64.50;H,6.73;N,12.51.

A mixture of the material prepared in the previous paragraph (1.56 g,7.0mmol), 1-(azepan-1yl)-4-chloro-2-phenyl-butan-1-one (2.0 g, 7.0 mmol),N,N-diisopropylethylamine (2.4 ml, 14.0 mmol) and potassium iodide (1.2g, 7.0 mmol) in 50 ml of anhydrous dimethylformamide was heated undernitrogen at 80° C. for five hours and then left at room temperatureovernight. The reaction was partitioned between ethyl acetate and water.The aqueous layer was separated and the organic layer washed five timeswith water. The organic layer was dried (MgSO₄) and the solvent removedunder reduced pressure to give 2.89 g of a brown foam. Purification ofthe foam on 400 g of silica gel (230-400 mesh) eluting with 75% ethylacetate-hexane gave 2.34 g of an off-white foam. The foam was dissolvedin diethyl ether and to this solution was added 7 ml of 1N ethereal HCl.The solid formed was collected by filtration, rinsed with diethyl ether,and dried under high vacuum to give as a light yellow solid the titlecompound (200 g, 58%) as a hydrochloride, hydrate, 0.08 diethyletherate, mp 105°-170° C.

Elemental Analysis for C₂₈ H₃₈ ClN₃ O₂ ·0.08 C₄ H₁₀ O; Calc'd: C, 69.41;H,7.98; N,8.87; Found: C,69.47;H,7.78;N,8.64.

EXAMPLE 31-Azepan-1-yl-4-((trans)-9-methyl-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-1-one

A mixture of 1,2,3,4-tetrahydro-9-methyl-pyrido[3,4-b]indolehydrochloride, prepared in the third paragraph of Example 2 (4.50 g, 20mmol), potassium carbonate (14.0 g, 100 mmol) and benzyl chloride (2.3ml, 20 mmol) in 45 ml of water plus 45 ml of tetrahydrofuran was stirredat room temperature overnight. The reaction was partitioned betweenwater and ethyl acetate. The organic layer was separated, extracted onetime with saturated sodium chloride, one time with water, dried (MgSO₄)and the solvent removed under reduced pressure to give 4.12 g of ayellow solid. Purification of the solid on 200 g of silica gel (230-400mesh) eluting with hexane-ethyl acetate gave 3.67 g (66%) of the2-benzyl derivative of the starting material as a white solid, mp109°-110° C.

Elemental Analysis for C₁₉ H₂₀ N₂ ; Calc'd: C,82.57;H,7.29;N,10.14;Found: C,82.29;H,7.29;N,10.01.

A solution of 1M BH₃.THF (49.2 ml, 49.2 mmol) was added under nitrogendropwise over ten minutes to a solution of the material prepared in theprevious paragraph (3.63 g, 13 mmol) in 250 ml of anhydroustetrahydrofuran at ice bath temperature. After the addition the coolingbath was removed and the reaction stirred at room temperature for thirtyminutes and then refluxed for thirty minutes. After cooling to roomtemperature the solvent was removed under reduced pressure. To thisresidue 80 ml of one to one glacial acetic acid-1N HCl was addedcautiously. After the evolution of gas ceased the reaction was refluxedfor fifteen minutes and then stirred overnight at room temperature. Thereaction was again refluxed for forty-five minutes and then cooled in anice bath before 50% aqueous NaOH was added until the reaction was basic.The reaction was extracted with methylene chloride, dried (MgSO₄) andthe solvent removed under reduced pressure to give 5 g of a clear oil.Purification of the oil on 600 g of silica gel (230-400 mesh) elutingwith 10% ethyl acetate-hexane gave 3.70 g of a white solid.Recrystallization of the solid from diisopropyl ether gave 2.61 g (71%)of the hexahydro derivative of the starting material as a white solid,mp 59°-60° C.

Elemental Analysis for C₁₉ H₂₂ N₂ ; Calc'd: C,81.97;H,7.97;N,10.06;Found: C,81.84;H,7.95;N,10.05.

A mixture of the material prepared in the preceding paragraph (2.48 g,8.9 mmol) and 1.2 g of 10% Pd/C in 250 ml of absolute ethanol washydrogenated at room temperature and 40 psi for 24 hours. The catalystwas removed by filtration through celite and the filtrate concentratedto dryness under reduced pressure to give 1.49 g of a tan solid.Recrystallization of the solid from diisopropyl ether gave 617 mg (37%)of the debenzylated derivative of the starting material as an off-whitesolid, mp 68°-70° C.

Elemental Analysis for C₁₂ H₁₆ N₂ ; Calc'd: C,76.55;H8.57;N,14.88;Found: C,76.47;H,8.68;N,14.77.

A mixture of the material produced in the previous paragraph (1.355 g,7.2 mmol), 1-(azepan-1-yl)-4-chloro-2-phenyl-butan-1-one (2.0 g, 7.2mmol), N,N-diisopropylethylamine (1.3 ml, 7.2 mmol) and potassium iodide(1.2 g, 7.2 mmol) in 30 ml of anhydrous dimethylformamide was heatedunder nitrogen at 80° C. for five hours. The reaction was partitionedbetween ethyl acetate and water. The organic layer was separated, washedfour times with water, dried (MgSO₄) and the solvent removed underreduced pressure to give 2.95 g of a brown solid. Purification of thesolid on 300 g of silica gel (230-400 mesh) eluting with 50%hexane-ethyl acetate gave 2.30 g of an off-white solid.Recrystallization of the solid two times from isopropyl alcohol gave0.542 g (17%) of the title compound as a white solid. NMR analysis ofthis material indicated it to be a single diastereomer, mp 111°-113° C.

Elemental Analysis for C₂₈ H₃₇ N₃ O; Calc'd: C,77.92;H,8.64;N,9.74;Found: C,77.52;H,8.70;N,9.63.

The mother liquor from the above recrystallization was purified by HPLC(hexane-isopropyl alcohol) to give 169 mg of a yellow oil. The oil wasdissolved in diethyl ether plus a small amount of CH₂ Cl₂. Oneequivalent of 1N ethereal HCl was added and the solvent was concentratedto approximately half its volume. Diethyl ether was added and a solidformed. The solid was collected by filtration, rinsed with diethyl etherand dried under high vacuum to give 88.4 mg of a brown solid. NMRanalysis indicated the solid to be the other diastereomer formed in thereaction, melting range 150°-200 C.

Elemental Analysis for C₂₈ H₃₇ N₃ O.HCl.4H₂ O.0.1C₄ H₁₀ O; Calc'd:C,62.30;H,8.65,N,7.67; Found: C,62.81;H,7.37;N,7.60.

EXAMPLE 41-Azepan-1-yl-4-((cis)-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-1-one

Triethylsilane (27.8 ml, 174 mmol) was added under nitrogen to asolution of 1,2,3,4-tetrahydro-9H-pyrido [3,4-b]indole (10.0 g, 58 mmol)in 150 ml of trifluoroacetic acid and the reaction stirred at 50° C. forapproximately five days. The solvent was removed under reduced pressureto give 96.88 g of a two phase oil. Purification of the oil by HPLCeluting with 2:1:1 ethyl acetate:methanol:ammonium hydroxide gave 3.83 gof the hexahydro derivative (trifluroacetic acid salt) of the startingmaterial as a white solid, mp 146°-149° C.

Elemental Analysis for C₁₁ H₁₄ N₂.CF₃ CO₂ H; Calc'd:C,54.17;H,5.24;N,9.72. Found: C,54.26;H,5.20;N,9.70.

A mixture of the material produced in the previous paragraph (4.0 g, 14mmol), 1-(azepan-1-yl)-4-chloro-2-phenyl-butan-1-one (3.89 g, 14 mmol),N,N-diisopropylethylamine (4.85 ml, 28 mmol) and potassium iodide (2.31g, 14 mmol) in 250 ml of anhydrous dimethylformamide was heated undernitrogen at 75° C. for six hours. The reaction was partitioned betweenethyl acetate and water. The organic layer was separated, washedmultiple times with water, dried (MgSO₄) and the solvent removed underreduced pressure to give 5.33 g of a brown oil. Purification of the oilby HPLC eluting with methanol-methylene chloride gave 1.14 g of a yellowoil. The oil was dissolved in diethyl ether containing a small amount ofmethylene chloride. One equivalent of ethereal HCl was added and thesolid formed was collected by filtration and dried under high vacuum togive the title compound as a light brown solid, hydrochloride, hydrate,0.2 diethyl etherate. NMR analysis and chiral HPLC showed the materialto be a mixture of diastereomers and their enantiomers, mp 105°-130° C.

Elemental Analysis for C₂₇ H35N₃ O.HCl.H₂ O.0.2C₄ H₁₀ O; Calc'd:C,68.57;H,8.28;N,8.63. Found: C,68.51;H,8.19;N,8.57.

EXAMPLE 51-Azepan-1-yl-4-((cis)-9-methyl-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3.4-b]indol-2-yl)-2-phenyl-butane-1-one

A solution of benzyl chloroformate (3.80 mL, 26.6 mmol) in 100 mL ofanhydrous dimethyl-formamide was added under nitrogen dropwise over twohours to a solution of the material prepared in paragraph 1 of Example 4(7.64 g, 26.6 mmol) and triethylamine (7.42, 53.2 mmol) in 100 ml ofanhydrous dimethylformamide at ice bath temperature. After the additionthe reaction was stirred at ice bath temperature for two hours and atroom temperature overnight. The reaction was diluted with ethyl acetate,washed multiple times with water, dried (MgSO₄) and the solvent removedunder reduced pressure to give 5.74 g of an oil. Purification of the oilon 450 g of silica gel (230-400 mesh) eluting with hexane-ethyl acetategave 2.04 g of a solid. Recrystallization of the solid from isopropylalcohol gave 1.44 g (18%) of the benzyloxycarbonyl derivative of thestarting material, mp 88°-90° C.

Elemental Analysis for C₁₉ H₂₀ N₂ O₂ ; Calc'd: C,74.00; H,6.54;N,9.08;Found: C,73.96;H,6.54;N,9.03.

Sodium hydride (271 mg of a 60% oil dispersion containing 6.78 mmol) wasadded in portions tinder nitrogen to a solution of the material preparedin the preceding paragraph (1.74g, 5.65 mmol) in 20 ml anhydrousdimethylformamide at room temperature. After the addition, the reactionwas stirred a room temperature for two hours. Methyl iodide (1.06 ml,16.95 mmol) was added and the reaction stirred at room temperatureovernight. The reaction was diluted with ethyl acetate, washed multipletimes with water, dried (MgSO₄) and the solvent removed under reducedpressure to give 1.0g of an oil. Purification of the oil on 450 g ofsilica gel (230-400 mesh) eluting with hexane-ethyl acetate gave 850 mg(47%) of the methyl derivative of the starting material as a clear oil,MS m/e 322[M⁺ ].

Elemental Analysis for C₂₀ H₂₂ N₂ O₂ ; Calc'd: C,74.51;H,6.88;N,8.69;Found: C,73.35;H,6.85;N,8.52.

A mixture of the material prepared in the preceding paragraph (800 mg,2.48 mmol) and 120 mg of 10% Pd/C in 80 ml of ethanol was hydrogenatedat room temperature and 40 psi for 17 hours. The catalyst was removed byfiltration through celite and the solvent was removed under reducedpressure to give 426 mg (91%) of a brown oil which was used in the nextstep without purification.

A mixture of the material prepared in the preceding paragraph (382 mg,2.03 mmol), 1-azepan-1-yl)-4-chloro-2-phenyl-butan-1-one (568 mg, 2.03mmol), N,N-diisopropylethylamine (353 μl, 2.03 mmol)and potassium iodide(337 mg, 2.03 mmol) in 15 ml of anhydrous dimethylformamide was stirredunder nitrogen at 80° C. for five hours. The reaction was partitionedbetween ethyl acetate and water. The aqueous layer was separated and theorganic layer washed multiple times with water. The organic layer wasdried (MgSO₄) and the solvent removed under reduced pressure to give 739mg of a brown oil. Purification of the oil on 200 g of silica gel(230-400 mesh) eluting with ethyl acetate-methylene chloride gave 361 mgof an off-white solid. This solid was further purified by triturationwith hexane to give 205 mg of a solid. The solid (195 rag, 0.45 mmol)was dissolved in diethyl ether and 452 μl (0.45 mmol) of 1N ethereal HClwas added. The solid formed was collected by filtration and dried underhigh vacuum to give as an off-white solid the title compound (120 mg, ₁₂%) as a hydrochloride, sesquihydrate, 0.2 diethyl etherate, MS,m/e 431(M⁺ -HCl).

Elemental Analyses for C₂₈ H₃₇ N₃ O.HCl.1.5H₂ O.0.2C₄ H₁₀ O; Calc'd:C,67.84;H,8.30;N,₈.24; Found: C,68.09;H,8.43;N,8.48.

What is claimed is:
 1. A compound of the formula: ##STR4## where R₁ andR₅ are independently hydrogen, fluorine, chlorine, bromine, iodine,trifluoromethyl, cyano, nitro, CO₂ H, C₁ -C₆ alkyl, C₂ -C₁₀ alkenyl, C₁-C₆ alkoxy, C₃ -C₈ cycloalkyl, cycloalkylalkyl where the alkyl group isof 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms,C₃ -C₈ cycloalkyloxy, C₂ -C₇ alkylcarbonyl, C₂ -C₇ alkylcarbonyloxy, C₂-C₇ alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkylgroup, independently, contains 1 to 6 carbon atoms, tetrazolyl, --OH,--(CH₂)₁₋₆ OH, --SH, --NH₂ or --(CH₂)_(l-6) NR₈ R₉ where R₈ is hydrogen,C₁ -C₆ alkyl, C₂ -C₇ alkylcarbonyl, C₂ -C₇ alkoxycarbonyl and R₉ ishydrogen or C₁ -C₆ alkyl;R₂ is hydrogen or C₁ -C₆ alkyl; R₃ and R₄ arehydrogen or taken together with the carbon atoms to which they areattached form a double bond; R₆ and R₇ are independently H, C₁ -C₁₀alkyl, C₂ -C₁₀ alkenyl, C₃ -C₈ cycloalkyl, cycloalkylalkyl where thealkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 8carbon atoms or R₆ and R₇ taken together are polymethylene, which, withthe nitrogen atom to which they are attached, form a ring of 3 to 8atoms; or a pharmaceutically acceptable salt thereof.
 2. A compound ofclaim 1 in which R₁ and R₅, independently, represent hydrogen, fluorine,chlorine, bromine, trifluoromethyl, CO₂ H, C₁ -C₃ alkyl, C₁ -C₃ alkoxy,C₂ -C₄ alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which eachalkyl group, independently, contains 1 to 6 carbon atoms, --OH, --NH₂ or--(CH₂)₁₋₃ NR₈ R₉ where R₈ is hydrogen or C₁ -C₃ alkyl and R₉ ishydrogen or C₁ -C₃ alkyl; R₂ is H or C₁ -C₃ alkyl; R₃ and R₄ arehydrogen or taken together with the carbon atoms to which they areattached form a double bond; and R₆ and R₇, taken together arepolymethylene, which, with the nitrogen atom to which they are attached,form a ring of 5 to 8 atoms; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1 which is1-azepan-1-yl-2-phenyl-4-(1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-butan-1-oneor a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 which is1-azepan-1-yl-4-(9-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-1-oneor a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 which is1-azepan-1-yl-4-((trans)-9-methyl-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-1-oneor a pharmaceutically acceptable salt thereof.
 6. The compound of claim1 which is1-azepan-1-yl-4-((cis)-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-1-oneor a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 which is1-azepan-1-yl-4-((cis)-9-methyl-1,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-1-one.8. A pharmaceutical composition of matter comprising a compound of theformula: ##STR5## where R₁ and R₅ are independently hydrogen, fluorine,chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO₂ H, C₁ -C₆alkyl, C₂ -C₁₀ alkenyl, C₁ -C₆ alkoxy, C₃ -C₈ cycloalkyl,cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and thecycloalkyl group has 3 to 8 carbon atoms, C₃ -C₈ cycloalkyloxy, C₂ -C₇alkylcarbonyl, C₂ -C₇ alkylcarbonyloxy, C₂ -C₇ alkoxycarbonyl, mono- ordi-alkylaminocarbonyl in which each alkyl group, independently, contains1 to 6 carbon atoms, tetrazolyl, --OH, --(CH₂)₁₋₆ OH, --SH, --NH₂ or--(CH₂)₁₋₆ NR₈ R₉ where R₈ is hydrogen, C₁ -C₆ alkyl, C₂ -C₇alkylcarbonyl, C₂ -C₇ alkoxycarbonyl and R₉ is hydrogen or C₁ -C₆alkyl;R₂ is hydrogen or C₁ -C₆ alkyl; R₃ and R₄ are hydrogen or takentogether with the carbon atoms to which they are attached form a doublebond; R₆ and R₇ are independently H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃-C₈ cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbonatoms and the cycloalkyl group is 3 to 8 carbon atoms or R₆ and R₇ takentogether are polymethylene, which, with the nitrogen atom to which theyare attached, form a ring of 3 to 8 atoms; or a pharmaceuticallyacceptable salt thereof;and a pharmaceutically acceptable carriertherefor.